Prenatal alcohol exposure can disrupt development, leading to a spectrum of disorders that include facial dysmorphology, growth deficiencies and central nervous system dysfunction. Alcohol's adverse effect on brain development and associated cognitive abilities are among the most devastating consequences. Despite the known damaging effects of prenatal alcohol exposure, warning labels on alcohol-containing beverages, and other prevention efforts, women continue to drink alcohol during pregnancy. Thus, it is critical that we identify effective treatments and interventions for reducing the adverse consequences of prenatal alcohol exposure. Using an animal model, we have been investigating the effectiveness of the essential nutrient choline, as a treatment for fetal alcohol spectrum disorders (FASD). When administered during prenatal alcohol exposure, choline supplementation attenuates alcohol-related birth weight deficits, delayed development of reflexes, as well as impairments in cognitive functioning. More importantly, choline is also effective in reducing cognitive deficits associated with developmental alcohol exposure, even when administered after the alcohol insult and during postnatal development. Specifically, we find that postnatal choline supplementation can reduce the severity of overactivity, and deficits on a range of learning tasks observed in rats exposed to alcohol during development. These findings suggest that choline supplementation may serve as a relatively safe and effective treatment for FASD. We are only now beginning to investigate the neural correlates to the choline-related behavioral benefits and have yet to explore choline's mechanisms of action. The goal of this proposal is to further examine the beneficial effects of choline on development, with a focus on brain changes and potential mechanisms. First, we will examine the effects of developmental alcohol and choline on hippocampal and cortical development, particularly on development of cholinergic systems. Secondly, we will examine whether administration of donepezil, an acetylcholinesterase inhibitor which also increases cholinergic activity, can improve cognitive performance following early alcohol exposure. Finally, it is also possible that choline alters brain development by acting as a precursor to betaine and influencing the methionine/homocysteine cycle. We will examine if choline increases betaine and if betaine administration leads to similar beneficial effects as choline. Better understanding of how choline affects brain and behavioral development among subjects who have been exposed to alcohol during development is important as we translate this dietary treatment to clinical populations. PUBLIC HEALTH RELEVANCE: Prenatal alcohol exposure disrupts physical, brain and behavioral development, leading to a range of fetal alcohol spectrum disorders (FASD). The goal of the current proposal is to investigate interventions that can improve the cognitive functioning of individuals with FASD. This project has important implications for improving the quality of life of those exposed to alcohol prenatally.